We provided further evidence that TSSC3 overexpression induces autophagy, likely via the Src-mediated PI3K/Akt/mTOR pathway, and autophagy, at least partially, contributes to TSSC3-induced tumorigenesis and metastasis suppression in osteosarcoma, both in vitro and in vivo. The gene discussed is PHLDA2; the disease is osteosarcoma.